The molecular landscape of ETMR at diagnosis and relapse

Sander Lambo, Susanne N. Gröbner, Tobias Rausch, Sebastian M. Waszak, Christin Schmidt, Aparna Gorthi, July Carolina Romero, Monika Mauermann, Sebastian Brabetz, Sonja Krausert, Ivo Buchhalter, Jan Koster, Danny A. Zwijnenburg, Martin Sill, Jens-Martin Hübner, Norman Mack, Benjamin Schwalm, Marina Ryzhova, Volker Hovestadt, Simon Papillon-Cavanagh, Jennifer A. Chan, Pablo Landgraf, Ben Ho, Till Milde, Olaf Witt, Jonas Ecker, Felix Sahm, David Sumerauer, David W. Ellison, Brent A. Orr, Anna Darabi, Christine Haberler, Dominique Figarella-Branger, Pieter Wesseling, Jens Schittenhelm, Marc Remke, Michael D. Taylor, Maria J. Gil-da-Costa, Maria Łastowska, Wiesława Grajkowska, Martin Hasselblatt, Peter Hauser, Torsten Pietsch, Emmanuelle Uro-Coste, Franck Bourdeaut, Julien Masliah-Planchon, Valérie Rigau, Sanda Alexandrescu, Stephan Wolf, Xiao-Nan Li, Ulrich Schüller, Matija Snuderl, Matthias A. Karajannis, Felice Giangaspero, Nada Jabado, Andreas Deimling, David T. W. Jones, Jan O. Korbel, Katja Hoff, Peter Lichter, Annie Huang, Alexander J. R. Bishop, Stefan M. Pfister, Andrey Korshunov and Marcel Kool ()
Additional contact information
Sander Lambo: Hopp Children’s Cancer Center (KiTZ)
Susanne N. Gröbner: Hopp Children’s Cancer Center (KiTZ)
Tobias Rausch: Genome Biology Unit
Sebastian M. Waszak: Genome Biology Unit
Christin Schmidt: Hopp Children’s Cancer Center (KiTZ)
Aparna Gorthi: University of Texas Health at San Antonio
July Carolina Romero: University of Texas Health at San Antonio
Monika Mauermann: Hopp Children’s Cancer Center (KiTZ)
Sebastian Brabetz: Hopp Children’s Cancer Center (KiTZ)
Sonja Krausert: Hopp Children’s Cancer Center (KiTZ)
Ivo Buchhalter: German Cancer Research Center (DKFZ)
Jan Koster: Academic Medical Center
Danny A. Zwijnenburg: Academic Medical Center
Martin Sill: Hopp Children’s Cancer Center (KiTZ)
Jens-Martin Hübner: Hopp Children’s Cancer Center (KiTZ)
Norman Mack: Hopp Children’s Cancer Center (KiTZ)
Benjamin Schwalm: Hopp Children’s Cancer Center (KiTZ)
Marina Ryzhova: NN Burdenko Neurosurgical Institute
Volker Hovestadt: German Cancer Research Center (DKFZ)
Simon Papillon-Cavanagh: McGill University Health Center, McGill University
Jennifer A. Chan: University of Calgary
Pablo Landgraf: Faculty of Medicine and University Hospital Cologne, University of Cologne
Ben Ho: The Hospital for Sick Children
Till Milde: Hopp Children’s Cancer Center (KiTZ)
Olaf Witt: Hopp Children’s Cancer Center (KiTZ)
Jonas Ecker: Hopp Children’s Cancer Center (KiTZ)
Felix Sahm: Hopp Children’s Cancer Center (KiTZ)
David Sumerauer: University Hospital Motol
David W. Ellison: St Jude Children’s Research Hospital
Brent A. Orr: St Jude Children’s Research Hospital
Anna Darabi: Lund University
Christine Haberler: Medical University of Vienna
Dominique Figarella-Branger: Aix-Marseille University, Neurophysiopathology Institute (INP), CNRS
Pieter Wesseling: Princess Máxima Center for Pediatric Oncology
Jens Schittenhelm: University Hospital of Tübingen
Marc Remke: German Cancer Research Center (DKFZ)
Michael D. Taylor: University of Toronto
Maria J. Gil-da-Costa: University Hospital São João Alameda Hernani Monteiro
Maria Łastowska: Children’s Memorial Health Institute
Wiesława Grajkowska: Children’s Memorial Health Institute
Martin Hasselblatt: University Hospital Münster
Peter Hauser: Semmelweis University
Torsten Pietsch: University of Bonn Medical Center
Emmanuelle Uro-Coste: Toulouse University Hospital
Franck Bourdeaut: INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Paris Sciences Lettres Research University, Curie Institute
Julien Masliah-Planchon: Curie Institute
Valérie Rigau: Montpellier University Medical Center
Sanda Alexandrescu: Harvard Medical School
Stephan Wolf: German Cancer Research Center (DKFZ)
Xiao-Nan Li: Baylor College of Medicine
Ulrich Schüller: University Medical Center, Hamburg-Eppendorf
Matija Snuderl: NYU Langone Health
Matthias A. Karajannis: The Stephen D. Hassenfeld Children’s Center for Cancer and Blood Disorders
Felice Giangaspero: Sapienza University of Rome
Nada Jabado: McGill University Health Center, McGill University
Andreas Deimling: Hopp Children’s Cancer Center (KiTZ)
David T. W. Jones: Hopp Children’s Cancer Center (KiTZ)
Jan O. Korbel: Genome Biology Unit
Katja Hoff: Charité University Medicine
Peter Lichter: German Cancer Research Center (DKFZ)
Annie Huang: The Hospital for Sick Children
Alexander J. R. Bishop: University of Texas Health at San Antonio
Stefan M. Pfister: Hopp Children’s Cancer Center (KiTZ)
Andrey Korshunov: Heidelberg University Hospital
Marcel Kool: Hopp Children’s Cancer Center (KiTZ)

Nature, 2019, vol. 576, issue 7786, 274-280

Abstract: Abstract Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2–4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

Date: 2019
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DOI: 10.1038/s41586-019-1815-x

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